Comparative studies of vertebrate scavenger receptor class B type 1: a high-density lipoprotein binding protein

Roger S Holmes,^1,2 Laura A Cox<sup>1

1</sup>Department of Genetics and Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA; ²School of Biomolecular and Physical Sciences, Griffith University, Nathan, Queensland, Australia

Abstract: Scavenger receptor class B type 1 protein (SCARB1) plays an essential role in cholesterol homeostasis and functions in binding high density lipoprotein cholesterol (HDL) in liver and other tissues of the body. SCARB1 also functions in lymphocyte homeostasis and in the uptake of hepatitis C virus (HCV) by the liver. A genetic deficiency of this protein results in autoimmune disorders and significant changes in blood cholesterol phenotype. Comparative SCARB1 amino acid sequences and structures and SCARB1 gene locations were examined using data from several vertebrate genome projects. Vertebrate SCARB1 sequences shared 50%–99% identity as compared with 28%–31% sequence identities with other CD36-like superfamily members, ie, SCARB2 and SCARB3 (also called CD36). At least eight N-glycosylation sites were conserved among most of the vertebrate SCARB1 proteins examined. Sequence alignments, key amino acid residues, and conserved predicted secondary structures were also studied, including: cytoplasmic, transmembrane, and exoplasmic sequences; conserved N-terminal and C-terminal transmembrane glycines which participate in oligomer formation; conserved cystine disulfides and a free SH residue which participates in lipid transport; carboxyl terminal PDZ-binding domain sequences (Ala507-Arg/Lys508-Leu509); and 30 conserved proline and 18 conserved glycine residues, which may contribute to short loop formation within the exoplasmic HDL-binding sequence. Vertebrate SCARB1 genes usually contained 12 coding exons. The human SCARB1 gene contained CpG islands, micro RNA binding sites, and several transcription factor binding sites (including PPARG) which may contribute to the high level (13.7 times the average) of gene expression. Phylogenetic analyses examined the relationships and potential evolutionary origins of the vertebrate SCARB1 gene with vertebrate SCARB2 and vertebrate and invertebrate SCARB3 (CD36) genes. These suggested that SCARB1 originated in a vertebrate ancestral genome from a gene duplication event of an ancestral invertebrate CD36 gene.

Keywords: vertebrates, amino acid sequence, SCARB1, evolution, high-density lipoprotein receptor